The prevalence, morbidity, and mortality of arterial hypertension are disproportionately high in the African-American population. Essential hypertension is a polygenic and heterogeneous disorder. In particular, African-Americans display an amplified blood pressure response to salt. The cellular and molecular mechanisms of salt-sensitive hypertension in humans remain poorly defined and our knowledge of potential genetic mechanisms remains incomplete. We recently observed an augmented blood pressure response to a salt challenge in healthy non-obese African- Americans females as compared to Whites. African-Americans also had significantly higher intracellular Na and depressed activity of the Na pump (86 Rb uptake)as compared to Whites suggesting these may be important phenotypic markers of salt-sensitive hypertension. In fact, an increase in intracellular Na was positively correlated with the increases in systolic blood pressure following one week of low salt vs one week of high salt diet in African-Americans but not in Whites. The inverse relationship was noted for the Na pump in African-Americans. The proposed study will carry out genetic studies of sibships with at least two hypertensive embers ascertained from the African-American population. Emphasizing model- free approaches to genetic linkage analysis based upon hypertensive sibling pairs, candidate genes that have been associated with salt-sensitive hypertension in either human or animal studies will be evaluated with respect to these intermediate phenotypes, and blood pressure responses to a salt challenge. The aims of this proposal are: l) To characterize the intermediate phenotypes of salt sensitivity, intracellular Na, sodium pump activity, and protein expression in a cohort of 500 hypertensive siblings in 160 sibships and to genotype these individuals; wherever possible, parents of these subjects will also be genotyped in order to better establish identity by descent relationships. 2) To assess linkage of the various candidate loci with intermediate phenotypes relating to the magnitude of blood pressure change with a salt challenge using univariate and multivariate approaches. The overall aim of this project is to improve our understanding of the genetic basis and phenotypic characterization of salt-sensitive hypertension in African Americans. To this end, careful analytic attention will be paid to the development of improved phenotype definition, as well as to the consideration of gene-gene and gene-environment interaction.